This invention relates to a process for the crystallization from solution of a chemical species having multiple conformations with steric hindrance to transitions between such conformations.
The vast majority of organic compounds are capable of adopting different conformations, generally as a result of rotations about sigma bonds. Where the compounds contain bulky groups however there is significant steric hindrance to such rotations and as a result transitions between stable (or metastable) conformations occur relatively slowly.
For crystallization of a substance to occur, the substance must adopt the conformation required by the crystalline structure. Accordingly, crystallization of sterically hindered compounds can take place relatively slowly. A high degree of supersaturation is normally required for acceleration of crystallization, resulting in limited purity in the crystalline product.
This is the case for example with the iodophenyl compounds commonly used as X-ray contrast agents and is particularly true for the so-called dimeric compounds which contain two iodophenyl groups per molecule, e.g. compounds such as iodixanol and iotrolan, which may take days to crystalize.
As a result, the manufacture of such compounds is extremely demanding in terms of time and equipment.
We have now found that crystallization of such sterically hindered compounds from solution may be accelerated, and/or the need for a high degree of supersaturation may be reduced, by crystallization with high thermal energy. The necessary thermal energy can be achieved by use of a boiling solvent (or boiling solvent mixture) or crystallization under pressure.
Crystallization under pressure is performed at temperatures above the boiling point (at atmospheric pressure) of the solution.
The invention thus provides a time-saving method and/or a method which will improve the purity of the product.
Thus viewed from one aspect the invention provides a process for the crystallization of a sterically hindered organic compound from a saturated or more preferably supersaturated solution of said compound in a solvent therefor, characterised in that crystallization is effected with high thermal energy.
One preferred aspect of the invention provides a process for the crystallization of a sterically hindered organic compound from a saturated or more preferably supersaturated solution of said compound in a solvent therefor, characterised in that crystallization is effected under elevated pressure at a temperature above the boiling point of said solution at atmospheric pressure (ie. ambient pressure, e.g. 1 bar) and up to the boiling point of said solution at said elevated pressure.
The necessary thermal energy may also be achieved by crystallization at the boiling point of the solvent or solvent mixture at atmospheric conditions. Under such working conditions the thermal energy input is limited by the boiling point of the solvent or solvent mixture used.
Thus a further preferred aspect of the invention provides a process for the crystallization of a sterically hindered organic compound from a saturated or more preferably supersaturated solution of said compound in a solvent therefor, characterised in that crystallization is effected at the boiling point of the solvent or solvent mixture used.
In the processes of the invention, the supersaturated solution may for example be produced from a non-saturated solution (e.g. by evaporation of a solvent or by cooling), or by dissolving amorphous material at elevated temperatures, or by the addition of a material (e.g. an anti-solvent) which reduces the solubility in the solvent system of the substance to be crystallized.
Crystallization from the supersaturated solution may be started by the use of a crystallization initiator, e.g. seed crystals of the sterically hindered compound. These may be added to the supersaturated solution before, during or after temperature and pressure are raised.
The solvent used in the processes of the invention may be a single solvent or a solvent mixture. Any solvent or solvent mixture capable of forming a liquid solution of the sterically hindered compound may be used although solvents such as water, alcohols, ketones, esters, ethers, and hydrocarbons are preferred, especially water, alcohols, alcohol-ethers, ethers and ketones, e.g. C1-4 alcohols.
Examples of suitable solvents include water, methanol, ethanol, n-propanol, isopropanol, n-butanol, i-butanol, sec-butanol, t-butanol, pentanols including isoamyl alcohol, methoxyethanol, ethylene glycol, propylene glycol, acetone, ethyl-methyl ketone, formaldehyde, acetaldehyde, dimethyl ether, diethylether, methylethyl-ether, tetrahydrofuran, ethylacetate, methyl cyanide, dimethylsulphoxide, dimethylformamide, benzene, toluene, xylene, n-hexane, cyclohexane, n-heptane, etc.
Especially preferably, the solvent comprises one or more C1-6 alkanols, alkoxyalkanols, linear or cyclic ethers, optionally together with a minor quantity (e.g. up to 10 wt %) of water.
Especially preferably, the solvent or solvent mixture used is a low-boiling or moderate boiling point material, e.g. having a boiling point of xe2x88x9210 to +100xc2x0 C. at ambient pressure, especially 30 to 80xc2x0 C., particularly 40 to 70xc2x0 C. The solvent or solvent mixture however should be stable at the temperature and pressure conditions used. It is also preferred that the crystallization be effected at a temperature below 200xc2x0 C., especially below 150xc2x0 C. and most preferably below 120xc2x0 C., and for crystallization under pressure that this be a temperature at least 10xc2x0 particularly at least 15xc2x0 C. above the boiling point of the solution under ambient pressure.
An added advantage of the pressure crystallization aspect of the invention is that the solubility of the sterically hindered compound is higher at the temperatures used than at temperatures below the boiling point of the solution at ambient pressure. As a result, the quantity of solvent used can be reduced as can the volume of the crystallizer vessel. Moreover solvents in which the sterically hindered compound is only relatively poorly soluble under ambient conditions may be usable and as a result it may be feasible to use more environmentally friendly solvent systems for crystallization (or recrystallization).
The sterically hindered compound crystallized according to the processes of the invention will preferably be a compound having at ambient temperature in solution (e.g. in water, C1-4 alcohol or C1-4 ether) at least two stable conformations with an activation energy at ambient conditions of at least 50 kJ/mole, preferably at least 80 kJ/mole, and preferably no more than 200 kJ/mole, for transition between these conformations. This activation energy may be calculated by standard techniques of quantum chemistry, etc.
In general, the processes of the invention are suitable for compounds which have a high activation energy for crystal growth, e.g. higher than 50 kJ/mole.
Examples of suitable compounds include hydroxyalkyl and/or acylamino and/or alkylaminocarbonyl derivatives of 2,4,6-triiodophenyl monomers and dimers such as those proposed or used as X-ray contrast agents (and in particular the non-ionic agents), for example diatrizoate, iobenzamate, iocarmate, iocetamate, iodamide, iodipamide, iodixanol, iohexol, iopentol, ioversol, iopamidol, iotrolan, iodoxamate, ioglicate, ioglycamate, iomeprol, iopanoate, iophenylate, iopromide, iopronate, ioserate, iosimide, iotasul, iothalamate, iotroxate, ioxaglate, ioxitalamate, metrizamide and metrizoate, as well as the monomers and dimers of WO96/09285 and W096/09282.
Besides such iodinated x-ray contrast agents, the processes of the invention are also applicable to crystallization of other sterically hindered compounds, in particular pharmaceutical compounds, especially substances having highly restricted side chain rotations or other conformational changes. Such substances should of course be crystallized at temperatures at which they are stable. The processes moreover are applicable to all substances with low solubility in a selected low-boiling solvent regardless of the activation energy of the steric changes.
The pressure applied in the pressure crystallization aspect of the invention will conveniently be such as to ensure that the boiling point of the saturated or supersaturated solution is raised relative to the boiling point at ambient pressure by at least 10xc2x0 C., especially at least 15xc2x0 C. and more especially at least 20xc2x0 C. The maximum pressure will generally be dictated by design constraints on the apparatus used but in general an overpressure of 0.05 to 20 bar, particularly 0.2 to 10 bar, especially 1.5 to 6 bar may be used.
The crystallization should therefore be performed in a vessel capable of withstanding the temperature and pressure conditions used. In general a stainless steel batch or continuous reactor equipped for stirring, heating and provided with means for applying and releasing pressure may be used.
In the xe2x80x9cboiling pointxe2x80x9d aspect of the invention the choice of solvent will reflect not only the capability to form a liquid mixture, but also the need for thermal energy in order to achieve an effective crystallization process. The process is especially suitable for the crystallization of iodixanol with the solvent being methanol or a mixture of methanol (0-100% by volume), propan-2-ol (0-80% by volume) and water (0-10% by volume).
The invention will now be described with reference to the following non-limiting Examples: